{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:20:19Z","timestamp":1787793619780,"version":"build-2784847793"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":70,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K08572"],"award-info":[{"award-number":["JP22K08572"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Spondyloarthritis (SpA) is a chronic inflammatory disorder characterized by enthesitis of axial and peripheral joints. Although genetic factors, bacterial infection, dysbiosis, and mechanical stress contribute to its development, the role of epigenetic regulation remains poorly understood. DNA methylation has been implicated in immune dysregulation, and the DNA methyltransferase inhibitor, decitabine (DAC), has demonstrated therapeutic effects in autoimmune disease models. This study aimed to evaluate the effect of DAC in the SpA-resembling SKG\/Jcl (SKG) mouse model and elucidate the immunological mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SpA-like arthritis was induced in SKG mice via intraperitoneal injection of curdlan (1,3-\u03b2-glucan aggregates). DAC (1\u00a0mg\/kg) was administered weekly. Arthritis severity and histopathological changes were evaluated in the limb joints and tail, and histopathological enthesitis scores were assessed in the limb joints. Splenic T-cell profiles were analyzed by flow cytometry. CD4\u207a T cells were stimulated in vitro with DAC to assess cytokine production. To investigate epigenetic regulation, reduced representation bisulfite sequencing (RRBS) and RNA-seq were performed on Achilles tendon tissue containing enthesis. Local expression of IL-17 and vasoactive intestinal peptide receptor 1 (VIPR1) in peripheral entheses was assessed by immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DAC treatment significantly reduced arthritis severity and improved histopathological findings, including synovial hyperplasia, inflammatory cell infiltration, bone erosion, and cartilage loss. Peripheral enthesitis at the Achilles tendon insertion sites was also reduced. Flow cytometric analysis demonstrated that the DAC-treated group reduced IL-17\u00a0A expression in splenic CD4\u207a T cells during the early phase (weeks 4\u20138) and decreased PD-1 expression in regulatory T cells (Tregs) at week 12. In vitro, DAC suppressed IL-17\u00a0A secretion and enhanced TGF-\u03b2 production in stimulated splenic CD4\u207a T cells. Integrated RRBS and RNA-seq analyses identified\n                      <jats:italic>Vipr1<\/jats:italic>\n                      as a DAC-responsive gene, showing significant hypomethylation (\u0394methylation\u2009\u2265\u2009\u2212\u200925%) and concordant transcriptional upregulation (log\u2082FC\u2009&gt;\u20091) in the entheses of DAC-treated mice. Immunohistochemical analysis of the ankle entheses revealed decreased IL-17\u00a0A expression and increased VIPR1 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      DAC ameliorated SpA in SKG mice, possibly through suppression of Th17 responses and epigenetic upregulation of\n                      <jats:italic>Vipr1<\/jats:italic>\n                      , and may be associated with improved Treg-associated regulation. These findings highlight an important role of DNA methylation in SpA pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-026-03848-0","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:27:39Z","timestamp":1781756859000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation inhibitor decitabine ameliorates spondyloarthritis by suppressing Th17 responses and epigenetically upregulating VIPR1 in SKG mice"],"prefix":"10.1186","volume":"28","author":[{"given":"Hoshiko","family":"Furusawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goh","family":"Murayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Nojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiga","family":"Kuga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukitomo","family":"Hagiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makio","family":"Kusaoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurisu","family":"Tada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Yamaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"issue":"7","key":"3848_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11926-018-0751-3","volume":"20","author":"A Watad","year":"2018","unstructured":"Watad A, et al. Enthesitis: Much More Than Focal Insertion Point Inflammation. Curr Rheumatol Rep. 2018;20(7):41.","journal-title":"Curr Rheumatol Rep"},{"issue":"3","key":"3848_CR2","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/mr\/roab057","volume":"32","author":"M Kusuda","year":"2022","unstructured":"Kusuda M, Haroon N, Nakamura A. Complexity of enthesitis and new bone formation in ankylosing spondylitis: current understanding of the immunopathology and therapeutic approaches. Mod Rheumatol. 2022;32(3):484\u201392.","journal-title":"Mod Rheumatol"},{"issue":"9","key":"3848_CR3","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.3899\/jrheum.151133","volume":"43","author":"E Hayashi","year":"2016","unstructured":"Hayashi E, et al. Involvement of Mucosal-associated Invariant T cells in Ankylosing Spondylitis. J Rheumatol. 2016;43(9):1695\u2013703.","journal-title":"J Rheumatol"},{"key":"3848_CR4","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jaut.2019.04.022","volume":"102","author":"P Coit","year":"2019","unstructured":"Coit P, et al. Genome-wide DNA methylation analysis in ankylosing spondylitis identifies HLA-B*27 dependent and independent DNA methylation changes in whole blood. J Autoimmun. 2019;102:126\u201332.","journal-title":"J Autoimmun"},{"issue":"1","key":"3848_CR5","doi-asserted-by":"publisher","first-page":"e000628","DOI":"10.1136\/rmdopen-2017-000628","volume":"4","author":"M Vecellio","year":"2018","unstructured":"Vecellio M, et al. Evidence for a second ankylosing spondylitis-associated RUNX3 regulatory polymorphism. RMD Open. 2018;4(1):e000628.","journal-title":"RMD Open"},{"key":"3848_CR6","doi-asserted-by":"publisher","first-page":"1084614","DOI":"10.3389\/fphar.2023.1084614","volume":"14","author":"H Feng","year":"2023","unstructured":"Feng H, et al. Adverse events of tumor necrosis factor alpha inhibitors for the treatment of ankylosing spondylitis: A meta-analysis of randomized, placebo-controlled trials. Front Pharmacol. 2023;14:1084614.","journal-title":"Front Pharmacol"},{"issue":"9","key":"3848_CR7","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1136\/annrheumdis-2019-215356","volume":"78","author":"DG McGonagle","year":"2019","unstructured":"McGonagle DG, et al. The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann Rheum Dis. 2019;78(9):1167\u201378.","journal-title":"Ann Rheum Dis"},{"key":"3848_CR8","doi-asserted-by":"publisher","first-page":"1488357","DOI":"10.3389\/fimmu.2025.1488357","volume":"16","author":"F Ciccia","year":"2025","unstructured":"Ciccia F, et al. JAK inhibition and axial spondyloarthritis: new steps on the path to understanding pathophysiology. Front Immunol. 2025;16:1488357.","journal-title":"Front Immunol"},{"key":"3848_CR9","doi-asserted-by":"crossref","unstructured":"Cedar H, Sabag O, Reizel Y. The role of DNA methylation in genome-wide gene regulation during development. Development. 2022;149(2):dev200118.","DOI":"10.1242\/dev.200118"},{"key":"3848_CR10","doi-asserted-by":"publisher","first-page":"757318","DOI":"10.3389\/fcell.2021.757318","volume":"9","author":"J Li","year":"2021","unstructured":"Li J, et al. Insights Into the Role of DNA Methylation in Immune Cell Development and Autoimmune Disease. Front Cell Dev Biol. 2021;9:757318.","journal-title":"Front Cell Dev Biol"},{"key":"3848_CR11","doi-asserted-by":"publisher","first-page":"1482728","DOI":"10.3389\/fimmu.2024.1482728","volume":"15","author":"S Mu","year":"2024","unstructured":"Mu S, et al. Autoimmune disease: a view of epigenetics and therapeutic targeting. Front Immunol. 2024;15:1482728.","journal-title":"Front Immunol"},{"key":"3848_CR12","doi-asserted-by":"crossref","unstructured":"Petralia MC et al. Effects of Treatment with the Hypomethylating Agent 5-aza-2\u2019-deoxycytidine in Murine Type II Collagen-Induced Arthritis. Pharmaceuticals (Basel). 2019;12(4):174.","DOI":"10.3390\/ph12040174"},{"key":"3848_CR13","doi-asserted-by":"crossref","unstructured":"Huang YS et al. Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis. Proc Natl Acad Sci U S A. 2021;118(19):e2100939118.","DOI":"10.1073\/pnas.2100939118"},{"issue":"1","key":"3848_CR14","doi-asserted-by":"publisher","first-page":"259","DOI":"10.4049\/jimmunol.182.1.259","volume":"182","author":"G Lal","year":"2009","unstructured":"Lal G, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259\u201373.","journal-title":"J Immunol"},{"issue":"34","key":"3848_CR15","doi-asserted-by":"publisher","first-page":"56802","DOI":"10.18632\/oncotarget.18063","volume":"8","author":"X Wang","year":"2017","unstructured":"Wang X, et al. Decitabine inhibits T cell proliferation via a novel TET2-dependent mechanism and exerts potent protective effect in mouse auto- and allo-immunity models. Oncotarget. 2017;8(34):56802\u201315.","journal-title":"Oncotarget"},{"issue":"12","key":"3848_CR16","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1002\/jcp.24641","volume":"229","author":"K Mangano","year":"2014","unstructured":"Mangano K, et al. Hypomethylating agent 5-aza-2\u2019-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models. J Cell Physiol. 2014;229(12):1918\u201325.","journal-title":"J Cell Physiol"},{"issue":"6","key":"3848_CR17","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.berh.2018.07.004","volume":"31","author":"MA Rahman","year":"2017","unstructured":"Rahman MA, Thomas R. The SKG model of spondyloarthritis. Best Pract Res Clin Rheumatol. 2017;31(6):895\u2013909.","journal-title":"Best Pract Res Clin Rheumatol"},{"issue":"1","key":"3848_CR18","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s13075-022-02844-4","volume":"24","author":"Y Tabuchi","year":"2022","unstructured":"Tabuchi Y, et al. Oral dextran sulfate sodium administration induces peripheral spondyloarthritis features in SKG mice accompanied by intestinal bacterial translocation and systemic Th1 and Th17 cell activation. Arthritis Res Ther. 2022;24(1):176.","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"3848_CR19","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.jbspin.2017.11.008","volume":"85","author":"H Jeong","year":"2018","unstructured":"Jeong H, et al. Spondyloarthritis features in zymosan-induced SKG mice. Joint Bone Spine. 2018;85(5):583\u201391.","journal-title":"Joint Bone Spine"},{"issue":"6","key":"3848_CR20","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1136\/annrheumdis-2020-219247","volume":"80","author":"S Hayer","year":"2021","unstructured":"Hayer S, et al. SMASH\u2019 recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models. Ann Rheum Dis. 2021;80(6):714\u201326.","journal-title":"Ann Rheum Dis"},{"key":"3848_CR21","unstructured":"van der Kraan PM et al. Degenerative knee joint lesions in mice after a single intra-articular collagenase injection: A new model of osteoarthritis. Int J Exp Pathol. 1990;71:19\u201331."},{"issue":"7","key":"3848_CR22","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1002\/art.38638","volume":"66","author":"H Benham","year":"2014","unstructured":"Benham H, et al. Interleukin-23 Mediates the Intestinal Response to Microbial \u2424-1,3-Glucan and the Development of Spondyloarthritis Pathology in SKG Mice. Arthritis Rheumatol. 2014;66(7):1755\u201367.","journal-title":"Arthritis Rheumatol"},{"issue":"6","key":"3848_CR23","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1159\/000486859","volume":"24","author":"C Li","year":"2017","unstructured":"Li C, et al. Vasoactive Intestinal Peptide Protects Salivary Glands against Structural Injury and Secretory Dysfunction via IL-17A and AQP5 Regulation in a Model of Sjogren Syndrome. Neuroimmunomodulation. 2017;24(6):300\u20139.","journal-title":"Neuroimmunomodulation"},{"key":"3848_CR24","doi-asserted-by":"publisher","first-page":"729","DOI":"10.3389\/fendo.2019.00729","volume":"10","author":"RP Gomariz","year":"2019","unstructured":"Gomariz RP, et al. An Overview of VPAC Receptors in Rheumatoid Arthritis: Biological Role and Clinical Significance. Front Endocrinol (Lausanne). 2019;10:729.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"3848_CR25","doi-asserted-by":"publisher","first-page":"701862","DOI":"10.3389\/fimmu.2021.701862","volume":"12","author":"J Leceta","year":"2021","unstructured":"Leceta J, Garin MI, Conde C. Mechanism of Immunoregulatory Properties of Vasoactive Intestinal Peptide in the K\/BxN Mice Model of Autoimmune Arthritis. Front Immunol. 2021;12:701862.","journal-title":"Front Immunol"},{"key":"3848_CR26","doi-asserted-by":"publisher","first-page":"110337","DOI":"10.1016\/j.clim.2024.110337","volume":"266","author":"T Nishiyama","year":"2024","unstructured":"Nishiyama T, et al. Mechanisms of age-related Treg dysfunction in an arthritic environment. Clin Immunol. 2024;266:110337.","journal-title":"Clin Immunol"},{"key":"3848_CR27","doi-asserted-by":"publisher","first-page":"p1058738","DOI":"10.1155\/2019\/1058738","volume":"2019","author":"NL Lai","year":"2019","unstructured":"Lai NL, et al. The Proportion of Regulatory T Cells in Patients with Ankylosing Spondylitis: A Meta-Analysis. J Immunol Res. 2019;2019:p1058738.","journal-title":"J Immunol Res"},{"key":"3848_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mehy.2018.03.005","volume":"115","author":"H Guo","year":"2018","unstructured":"Guo H, et al. Ratio of CD147(high)\/CD147(low) in CD4(+)CD25(+) T cells: A potential biomarker for early diagnosis and prediction of response to therapy for autoimmune diseases. Med Hypotheses. 2018;115:1\u20134.","journal-title":"Med Hypotheses"},{"key":"3848_CR29","doi-asserted-by":"publisher","first-page":"37559","DOI":"10.1038\/srep37559","volume":"6","author":"H Guo","year":"2016","unstructured":"Guo H, et al. Functional defects in CD4(+) CD25(high) FoxP3(+) regulatory cells in ankylosing spondylitis. Sci Rep. 2016;6:37559.","journal-title":"Sci Rep"},{"issue":"6","key":"3848_CR30","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1189\/jlb.0605299","volume":"78","author":"M Delgado","year":"2005","unstructured":"Delgado M, et al. Vasoactive intestinal peptide generates CD4\u2009+\u2009CD25+ regulatory T cells in vivo. J Leukoc Biol. 2005;78(6):1327\u201338.","journal-title":"J Leukoc Biol"},{"issue":"3","key":"3848_CR31","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1007\/s12031-015-0517-6","volume":"56","author":"IV Seoane","year":"2015","unstructured":"Seoane IV, et al. Vasoactive Intestinal Peptide in Early Spondyloarthritis: Low Serum Levels as a Potential Biomarker for Disease Severity. J Mol Neurosci. 2015;56(3):577\u201384.","journal-title":"J Mol Neurosci"},{"issue":"12","key":"3848_CR32","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nrrheum.2017.188","volume":"13","author":"G Schett","year":"2017","unstructured":"Schett G, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13(12):731\u201341.","journal-title":"Nat Rev Rheumatol"},{"issue":"8","key":"3848_CR33","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1182\/blood.2020008477","volume":"138","author":"P Han","year":"2021","unstructured":"Han P, et al. Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia. Blood. 2021;138(8):674\u201388.","journal-title":"Blood"},{"issue":"8","key":"3848_CR34","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1002\/art.40877","volume":"71","author":"DM Toth","year":"2019","unstructured":"Toth DM, et al. Amelioration of Autoimmune Arthritis in Mice Treated With the DNA Methyltransferase Inhibitor 5\u2019-Azacytidine. Arthritis Rheumatol. 2019;71(8):1265\u201375.","journal-title":"Arthritis Rheumatol"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-026-03848-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-026-03848-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-026-03848-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:52:20Z","timestamp":1787791940000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13075-026-03848-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3848"],"URL":"https:\/\/doi.org\/10.1186\/s13075-026-03848-0","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"15 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experiments were approved by the Institutional Animal Care and Use Committee of Juntendo University (approval number: 2023225) and were conducted in accordance with institutional guidelines and the ARRIVE guidelines.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"157"}}